Fas-mediated killing of primary prostate cancer cells is increased by mitoxantrone and docetaxel. Mol Cancer Ther 2008 Sep;7(9):3018-28
Date
09/16/2008Pubmed ID
18790782DOI
10.1158/1535-7163.MCT-08-0335Scopus ID
2-s2.0-54049125364 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
Therapies for prostate cancer based on Fas (CD95) modulation have been under active development at the preclinical stage using immortalized cell lines. To address clinical applicability, the potential of 11 cultures of primary prostate cancer cells to be killed by Fas-mediated apoptosis was investigated. In addition, the effect of the chemotherapeutic agents mitoxantrone and docetaxel on this killing was determined. Apoptosis was induced in patient-derived, primary prostate cancer cells using effector cells engineered by recombinant lentivirus infection to express Fas ligand (FasL) and measured by 51Cr release assays. All cultured prostate cells were found to undergo Fas-mediated killing; cytotoxicity ranged from 12% to 87% after 6 h. These cells were significantly more sensitive to FasL-mediated killing than PC-3 cells. The basal expression of Fas or the expression of five inhibitors of apoptosis (c-FLIP, survivin, cellular inhibitors of apoptosis protein 1 and 2, and bcl-2) was not found to correlate with susceptibility to Fas-mediated killing. Both mitoxantrone and docetaxel were able to induce Fas receptor expression on primary prostate cancer cells, which translated into a 1.5- to 3-fold enhancement of apoptosis mediated by FasL. Whereas mitoxantrone increased the Fas-induced apoptotic response of all cultured prostate cells tested, docetaxel pretreatment was found to preferentially enhance the killing of bcl-2-expressing cells. These findings show that cultured primary prostate cancer cells are sensitive to Fas-mediated apoptosis. Furthermore, the incidence of apoptosis was found to be improved by combining Fas-mediated therapy with standard chemotherapeutic agents. These findings may have significant implications for prostate cancer therapy.
Author List
Symes JC, Kurin M, Fleshner NE, Medin JAAuthor
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Apoptosis
Apoptosis Regulatory Proteins
Drug Screening Assays, Antitumor
Drug Synergism
Fas Ligand Protein
Humans
Male
Mice
Mitoxantrone
Prostate
Prostatic Neoplasms
Taxoids
Tumor Cells, Cultured
Tumor Suppressor Protein p53
Up-Regulation
fas Receptor
